Betrixaban – the next direct factor Xa inhibitor?

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierr20 Download by: [FU Berlin] Date: 09 November 2016, At: 05:44 Expert Review of Hematology ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20 Betrixaban – the next direct factor Xa inhibitor? Martin Thoenes, Joan Minguet, Karin Bramlage, Peter Bramlage & Carmen Ferrero To cite this article: Martin Thoenes, Joan Minguet, Karin Bramlage, Peter Bramlage & Carmen Ferrero (2016): Betrixaban – the next direct factor Xa inhibitor?, Expert Review of Hematology, DOI: 10.1080/17474086.2016.1256194 To link to this article: http://dx.doi.org/10.1080/17474086.2016.1256194 Accepted author version posted online: 03 Nov 2016. Submit your article to this journal Article views: 8 View related articles View Crossmark data Page 1 of 28 Publisher: Taylor & Francis Journal: Expert Review of Hematology DOI: 10.1080/17474086.2016.1256194 Drug profile Betrixaban – the next direct factor Xa inhibitor? Martin Thoenes 1,2, Joan Minguet 3, Karin Bramlage 3, Peter Bramlage 2,3, Carmen Ferrero 2 1 Léman Research Institute, Neuhausen am Rheinfall, Switzerland 2 Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Sevilla, Spain 3 Institute for Pharmacology and Preventive Medicine, Mahlow, Germany 4 Department of Thoracic and Cardiovascular Surgery, West-German Heart Center Essen, University Hospital Essen, Essen, Germany Correspondence: Peter Bramlage Institute for Pharmacology and Preventive Medicine Page 2 of 28 Menzelstrasse 21, 15831 Mahlow, Germany Tel.: +49 3379 3147890 Fax: +49 3379 3147892 Email: [email protected] Abstract Introduction: Venous thromboembolism is a major global health burden. Since the 1930s, prevention of stroke and pulmonary embolism in these patients has been achieved using conventional anticoagulants, such as heparin and warfarin. However, in recent years, four direct non-vitamin K antagonist oral anticoagulants (DOACs) have entered the market as alternative treatment options. Betrixaban is a fifth DOAC looking to gain marketing approval in the near future, and may have several potentially beneficial properties. Areas covered: Here, we outline the metabolism, pharmacokinetics, and pharmacodynamics of betrixaban, and summarise its clinical efficacy and safety based on the results of phase II/III trials. Expert commentary: Betrixaban has been demonstrated to have antithrombotic activity that may make it a valuable addition to the repertoire of DOACs currently available. The low renal clearance and minimal hepatic metabolism of the drug may make it particularly beneficial for patients with renal or hepatic dysfunction. The lack of an effective reversal agent may be a more significant issue for betrixaban compared with the already approved DOACs as it has a longer terminal half-life. Available data suggest that continued development of betrixaban is justified; however, further large randomised clinical trials are essential in order to clarify its efficacy and safety. Page 3 of 28 Keywords: Betrixaban, factor Xa inhibitors, venous thromboembolism, anticoagulants, DOAC Page 4 of 28 1. INTRODUCTION 1.1 Venous thromboembolism and risk factors Venous thromboembolism (VTE) is major a health burden, which manifests as deep vein thrombosis (DVT), pulmonary embolism (PE), or a combination of the two [1]. It is thought to affect between 300,000 and 600,000 individuals in the USA per year [2], with an estimated annual incidence of between 104 and 183 per 100,000 person years in individuals of European ancestry [3]. Its occurrence is largely preventable, but significant morbidity and mortality result if appropriate prophylactic measures are not taken in a timely manner. Indeed, approximately 12% of deaths in France, Germany, Italy, Spain, Sweden, and the UK are attributable to VTE per year [4]. There are a number of known factors which may predispose a patient to VTE, each of which carry a different degree of risk and are used to assess the need for prophylactic action. Factors associated with a high risk of VTE include recent major surgery [5, 6], recent spinal cord trauma [7], fracture of the pelvis, hip, or long bones [8], immobility, hormone therapy, cancer and the co-existence of multiple lesser risk factors (such as advanced age [9], prior VTE, obesity, and hereditary thrombophilic syndromes) [10]. 1.2 Anticoagulants The significant but preventable morbidity and mortality associated with VTE necessitates early, appropriate management through anticoagulant administration. The goals of anticoagulation are to a) prevent stroke and PE, b) reduce morbidity, and c) minimise the development of post- Page 5 of 28 thrombotic syndrome (PTS) [11]. Anticoagulants have been recommended for this indication since the introduction of heparin in 1930 [12], with low molecular heparin (LMWH) and vitamin-K antagonists (e.g. warfarin) the most common treatment options used in current clinical practice [13]. Although many patients benefit substantially from these agents, they carry several limitations which have led to the development of novel alternatives. Direct non-vitamin K antagonist oral anticoagulants (DOACs, formerly “novel oral anticoagulants”) are direct factor IIa (FIIa) or direct factor Xa (FXa) inhibitors which are administered orally. They are currently approved for stroke and systemic embolism (SE) prophylaxis in non-valvular atrial fibrillation (NVAF) and for VTE prevention in a variety of indications [14, 15]. Several clinical trials have shown DOACs to be at least non-inferior to warfarin in terms of efficacy and safety and as rapid as heparin in terms of onset of action [16, 17]. Additionally, compared to conventional anticoagulants, DOACs have more predictable pharmacokinetics, with fewer drug-drug and drug-food interactions [1, 18], and as such may be more acceptable to patients and clinicians alike. However, it should be noted that a current lack of approved monitoring assays and only limited clinical experience are present disadvantages of DOACs. 1.3 Currently approved DOACs and betrixaban At the time of writing, four DOACs (i.e. dabigatran, rivaroxaban, apixaban, and edoxaban) have received market approval for stroke and SE prevention in patients with NVAF, and in the prevention of VTE. Although initial studies with each of these agents have yielded encouraging Page 6 of 28 results, concerns have been raised regarding the potential for drug accumulation due to a reliance on hepatic metabolism and renal clearance, particularly in patients with liver or kidney dysfunction [1]. Furthermore, drug interactions with inducers or inhibitors of cytochrome P450 (CYP450) have been identified for most approved DOACs, and their relatively short half-lives may place patients at risk of thrombosis if a dose is missed [1]. Conversely, early studies with betrixaban have demonstrated minimal metabolism in the liver (<1% of administered dose), a low rate of renal clearance (<7%), and a longer half-life (37 hours) compared to the aforementioned DOACs [19, 20] (Table 1). Betrixaban may therefore have several potential advantages over other DOACs, though given that the drug is still in the process of gaining market clearance and, as yet, no head-to-head comparisons exist, this remains to be conclusively demonstrated. Here, we present the pharmacological profile of betrixaban along with the results of its phase II [20, 21] and III [19] clinical trials, with the aim of evaluating its potential benefits and limitations in the management of thromboembolism. 2. PHARMACOLOGY 2.1 Development and pharmacodynamics Developed by Portola Pharmaceuticals Inc. (USA), betrixaban is a potent (Ki=0.117 pM) and selective inhibitor of FXa in either its free or prothrombinase-bound form [22]. It is derived from 1,N-(5-chloropyridin-2-yl)-2-(4-(N, N-dimethylcarbamimidoyl)-benzamido) benzamide [23]. Various analogues of this parent compound were obtained through an iterative process involving modification of the three phenyl rings. In addition to screening for FXa inhibitory Page 7 of 28 activity, each compound was evaluated for hERG channel affinity, which can result in potentially life-threatening cardiac arrhythmia. Based on its high FXa inhibition potency in combination with a low affinity for hERG channels (IC50=8.9 µM), compound PRT-054,021, later named betrixaban, was taken forward for further development [23]. 2.2 Pharmacokinetics Following oral administration, absorption of betrixaban occurs rapidly, with a bioavailability of 34% [1, 24]. Fatty foods and a high caloric breakfast have an affect on bioavailability, reducing the area under the curve (AUC) and peak serum concentration by up to 50% [1, 21, 24]. Peak plasma concentration is usually reached within 3-4 hours of betrixaban administration [1, 22, 25], with approximately 60% of the absorbed drug bound to plasma proteins, and a terminal half-life of 37 hours [1]. 2.3 Metabolism and clearance Approximately 13.7% of betrixaban undergoes metabolism via hydrolysis to form PRT063069 and PRT062802, the former of which exists predominantly as a circulatory metabolite, while the latter is the major metabolite detected in urine and faeces (AUC in human plasma: 24% and 34% of unchanged drug, respectively) [22]. Less than 1% is metabolised by CYP450 [1, 21], reducing the likelihood of drug interactions with inducers and inhibitors of these enzymes. Furthermore, the lack of hepatic metabolism may make betrixaban particularly suitable for Page 8 of 28 patients with liver dysfunction. The remaining 85.3% of the dose is excreted as an unchanged drug [22]. The vast majority of non-metabolised betrixaban (82-89%) is cleared in the faeces, with renal clearance accounting for <7% [22]. This is appreciably different to the clearance of the approved DOACs, for whom faecal clearance ranges between 26% and 88% and renal between 25% and >80% [1]. Thus, betrixaban may be of particular use in patients with renal insufficiency. In a nutshell, betrixaban is a single daily dose oral direct FXa inhibitor with minimal renal clearance, minimal hepatic metabolism, and a long half-life. The latter three properties are what make betrixaban stand out from the currently available DOACs, and if equivalent or superior safety and efficacy can be demonstrated, it may have a future place as a strong market competitor. However, the current lack of antidote needs to be urgently addressed, especially given the extremely long half-life of this agent and consequent risk of uncontrolled bleeding. 3. CLINICAL EFFICACY Four betrixaban clinical trials were identified during searches of clinicaltrials.gov and PubMed; two phase II studies [20, 21] and one phase III [26] study, plus one trial relating to the cardiac safety of the drug [27] (Table 2). Page 15 of 28 prevention in high-risk hospitalised patients that compares favourably with that of enoxaparin. However, the clinical studies performed so far have a number of limitations that prevent us from making accurate conclusions regarding the efficacy and safety of the drug. The relatively small population investigated in the EXPERT trial, along with the lack of statistical analysis, reduces the usefulness of the data [20]. Furthermore, the presence of DVT was established using venography, with no follow-up performed subsequent to this procedure. On the other hand, in the EXPLORE Xa trial, the combination of small group sizes and short follow-up period meant that the rate of stroke occurrence was too low to allow for meaningful inter-group comparisons [21]. As would be expected, the phase III APEX trial had fewer limitations, with a large population (N = 7,513) that allowed for robust statistical analysis [26]. This study provided evidence of a net clinical benefit of an extended duration of betrixaban over standard duration enoxaparin for acutely ill patients at risk of VTE, although statistical significance of the primary efficacy endpoint was narrowly missed. There remains insufficient information regarding the safety of betrixaban. While bleeding events were evaluated in each of the aforementioned trials, there was little attention paid to other safety endpoints. Data from the EXPLORE-Xa study showed a higher rate of diarrhoea for the betrixaban group compared to the warfarin group [21], indicating that there may be an increased risk of gastrointestinal side-effects resulting from the large proportion of unchanged drug that is excreted in the faeces. The same study also found a higher rate of premature study discontinuation for the betrixaban patients, although the reasons for this were not investigated further. As with all but one of the DOACs [29], the most notable safety concern for betrixaban is the lack of an approved reversal agent; however, this may be a more significant issue for Page 16 of 28 betrixaban, which has a longer terminal half-life. For patients that experience severe bleeding, or those that require emergency surgery, this is a potentially life-threatening predicament. There are a number of agents under investigation for their ability to reverse the anticoagulant effect of FXa inhibitors, the most notable of which is andexanet alfa (Portola Pharmaceuticals). This has been shown to effectively reverse the activity of apixaban and rivaroxaban [30], and is currently undergoing evaluation in a phase III trial [31]. The broad-spectrum reversal agent, ciraparantag (Perosphere), has been investigated for the reversal of edoxaban-induced anticoagulation. In a phase I study, it was shown to effectively achieve baseline haemostasis within 10–30 mins after administration [32]; a phase II study has recently been completed, with the results eagerly awaited [33]. How the efficacy and safety of betrixaban compares to those of the currently approved DOACs remains to be investigated. While the lack of head-to head comparison between the different DOACs is universal, the evidence for the efficacy and safety of those that have been approved is vastly superior to that available for betrixaban [16, 34-39]. This clearly demonstrates that further large-scale randomised trials will be necessary before marketing approval is likely to be considered. However, the available data indicate that continued development of betrixaban is justified. 7. FIVE-YEAR VIEW The phase III APEX trial provided encouraging evidence for benefits of betrixaban for patients with an acute illness that puts them at high risk of developing a VTE. As a result of this data, the Page 17 of 28 manufacturer is likely to apply for marketing approval in the USA and Europe in the near future. On the other hand, other indications for anticoagulation have received much less attention, and it is unlikely that betrixaban will receive approval for treatment of these within the next five years. There remain many issues associated with betrixaban that need to be evaluated further, including its use for patients with renal or hepatic dysfunction, the potential risk of gastrointestinal side-effects, drug-drug interactions, and drug-food interactions. One challenge that may be overcome within the next five years is the availability of an effective reversal agent. As the mechanism of anticoagulation of betrixaban is similar to that of the already approved FXa inhibitors, rivaroxaban, apixaban, and edoxaban, the development of a compound that disrupts this inhibitory process has long been pursued and is now at an advanced stage. 8. KEY ISSUES • Betrixaban is a direct non-vitamin K antagonist oral anticoagulant (DOAC) that works by directly inhibiting factor Xa in the coagulation cascade. • The phase III APEX trial demonstrated some clinical benefit of betrixaban compared to enoxaparin for the prevention of VTE in high-risk acutely ill patients. • Efficacy for the prevention of stroke in patients with non-valvular atrial fibrillation, or those who have undergone surgery such as a knee replacement, has not conclusively been established. Page 18 of 28 • Betrixaban has potential value for patients with renal or hepatic dysfunction, owing to reduced renal clearance and hepatic metabolism, respectively, in comparison to the currently available DOACs. • The long terminal half-life of betrixaban enables once-daily administration and reduces the risk of thrombosis caused by poor patient adherence. • Owing to the long terminal half-life, the absence of an effective reversal agent is of particular concern for betrixaban in comparison with other DOACs. • Further safety evaluation is necessary, as well as assessments of drug-drug and drugfood interactions. • Head-to-head comparisons with other DOACs would be highly informative. 9. INFORMATION RESOURCES For further information, related articles and relevant websites can be found in the reference list. Page 19 of 28 Funding This paper has not been funded. Declaration of Interest P Bramlage has received research support or consultancy fees from Bayer (the maker of rivaroxaban), Boehringer (dabigatran), Pfizer/Bristol Myers Squibb (apixaban) and Daiichi Sankyo (edoxaban). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. 10. REFERENCES *Article of interest **Article of considerable interest 1. Chan NC, Bhagirath V, Eikelboom JW. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015;11:343- 51. 2. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38(4 Suppl):S495-501. 3. Heit JA. Epidemiology of venous thromboembolism. Nature reviews Cardiology. 2015;12(8):464-74. 4. Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98(4):756-64. Page 20 of 28 5. Vaughan P, Gardner J, Peters F, Wilmott R. Risk factors for venous thromboembolism in general surgical patients. Isr Med Assoc J. 2002;4(11):1037-9. 6. O'Reilly RF, Burgess IA, Zicat B. The prevalence of venous thromboembolism after hip and knee replacement surgery. Med J Aust. 2005;182(4):154-9. 7. Merli GJ. MAnagement of deep vein thrombosis in spinal cord injury. Chest. 1992;102(6_Supplement):652S-7S. 8. Toker S, Hak DJ, Morgan SJ. Deep vein thrombosis prophylaxis in trauma patients. Thrombosis. 2011;2011:505373. 9. Linnemann B, Weingarz L, Schindewolf M, et al. Prevalence of established risk factors for venous thromboembolism according to age. J Vasc Surg Venous Lymphat Disord. 2014;2(2):131- 9. 10. Anderson FA, Jr., Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 Suppl 1):I9-16. 11. Patel K, Chang JS, Chun LJ. Deep Venous Thrombosis Treatment & Management 2016 [Accessed 07.10.2016]. Available from: http://emedicine.medscape.com/article/1911303- treatment. 12. Ita K. Transdermal delivery of heparin: Physical enhancement techniques. Int J Pharm. 2015;496(2):240-9. 13. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S- 84S. Page 21 of 28 14. Blann AD. Non-vitamin K antagonist oral anticoagulants (NOACs): a view from the laboratory. Br J Biomed Sci. 2014;71(4):158-67. 15. Saliba W. Non-vitamin K antagonist oral anticoagulants: new choices for patient management in atrial fibrillation. Am J Cardiovasc Drugs. 2015;15(5):323-35. 16. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-72. 17. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808. 18. Shields AM, Lip GY. Choosing the right drug to fit the patient when selecting oral anticoagulation for stroke prevention in atrial fibrillation. J Intern Med. 2015;278(1):1-18. 19. Cohen AT, Harrington R, Goldhaber SZ, et al. The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. Am Heart J. 2014;167(3):335-41. 20. Turpie AG, Bauer KA, Davidson BL, et al. A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb Haemost. 2009;101(1):68-76. **Phase II trial comparing betrixaban with enoxaparin for VTE prevention after total knee replacement surgery. 21. Connolly SJ, Eikelboom J, Dorian P, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J. 2013;34(20):1498-505. **Phase II trial comparing betrixaban with warfarin for the prevention of stroke in patients with NVAF. Page 22 of 28 22. Hutchaleelaha A, Ye C, Song Y, Lorenz T, Gretler DD, Lanbing JL. Metabolism and Disposition of Betrixaban and Its Lack of Interaction with Major CYP Enzymes. 54th ASH Annual Meeting and Exposition 2012:Abstract 2266. 23. Zhang P, Huang W, Wang L, et al. Discovery of betrixaban (PRT054021), N-(5- chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenz amide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett. 2009;19(8):2179-85. 24. Chan NC, Hirsh J, Ginsberg JS, Eikelboom JW. Betrixaban (PRT054021): pharmacology, dose selection and clinical studies. Future Cardiol. 2014;10(1):43-52. 25. Gomez-Outes A, Suarez-Gea ML, Lecumberri R, Terleira-Fernandez AI, Vargas-Castrillon E, Rocha E. Potential role of new anticoagulants for prevention and treatment of venous thromboembolism in cancer patients. Vasc Health Risk Manag. 2013;9:207-28. 26. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. New England Journal of Medicine. 2016;375(6):534- 44. **Phase III trial comparing betrixaban with enoxaparin for VTE prevention in acutely ill patients. 27. Morganroth J, Gretler DD, Hollenbach SJ, Lambing JL, Sinha U. Absence of QTc prolongation with betrixaban: a randomized, double-blind, placebo- and positive-controlled thorough ECG study. Expert Opin Pharmacother. 2013;14(1):5-13. 28. ICH harmonised tripartite guideline. The clinical evaluation of qt/qtc interval prolongation and proarrhythmic potential for non antiarrhythmic drugs e14. 2005 [Accessed 07.10.2016]. Available from: Page 23 of 28 http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Gu ideline.pdf. 29. Pollack CV, Jr., Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373(6):511-20. 30. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015. 31. A Study in Patients With Acute Major Bleeding to Evaluate the Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Direct and Indirect Oral Anticoagulants (NCT02329327) [Accessed 07.10.2016]. Available from: https://clinicaltrials.gov/ct2/show/NCT02329327?term=Andexanet+alfa&rank=3. 32. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban. New England Journal of Medicine. 2014;371(22):2141-2. 33. Study of PER977 Administered to Subjects With Steady State Edoxaban Dosing and Reanticoagulation With Edoxaban (NCT02207257) [Accessed 07.10.2016]. Available from: https://clinicaltrials.gov/ct2/show/NCT02207257?term=PER977&rank=3. 34. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51. 35. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92. 36. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91. Page 24 of 28 37. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-104. 38. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105(4):721-9. 39. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97. 40. Bathala MS, Masumoto H, Oguma T, He L, Lowrie C, Mendell J. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos. 2012;40(12):2250-5. 41. Mani H, Lindhoff-Last E. New oral anticoagulants in patients with nonvalvular atrial fibrillation: a review of pharmacokinetics, safety, efficacy, quality of life, and cost effectiveness. Drug Design, Development and Therapy. 2014;8:789-98. 42. Stacy ZA, Call WB, Hartmann AP, Peters GL, Richter SK. Edoxaban: a comprehensive review of the pharmacology and clinical data for the management of atrial fibrillation and venous thromboembolism. Cardiol Ther. 2016.